Malaria was responsible for 212 million of clinical cases in 2015. Plasmodium vivax is the most prevalent of the human malaria parasites and account for an estimated 41% of the malaria burden. P. vivax and P. ovale are characterized by their ability to produce undetectable dormant stages in the liver known as hypnozoites that can result in relapse infections weeks to months after the primary infection. Progress on the assessment of the molecular makeup of these parasite forms has been hindered by the biological constraints of these malaria parasite species that cannot be continuously cultured in vitro and to the challenging of studying relapsing in the limited number of experimental animal models available. The development of new tools for in vivo study of relapsing malaria parasites is, therefore, a research priority. This proposal will build on our experience working with simian malaria parasites and non-human primates to create a fully simianized mouse model to study relapsing parasites. The main goal is to develop a model that consistently reproduces the liver stage development of relapsing malaria parasites in vivo. In Aim 1 we will generate a simianized liver chimeric mice able to support the growth of simian relapsing malaria parasites. In Aim 2 we will assess the value of developing fully simianized mice to understand anti-liver stage immune responses with emphasis on the impact of pre-erythrocytic stage immunity on hypnozoites. The comprehensive characterization of experimental infections in the proposed animal model will provide opportunities to define novel biomarker for detection of hypnozoites and to understand compartmentalized immune responses in search of novel targets for interventions.